Theta Burst Stimulation as a Tool to Decrease Drinking in Treatment-seeking Alcohol Users

Theta Burst Stimulation as a Tool to Decrease Drinking in Treatment-seeking Alcohol Users

Sponsors

Lead Sponsor: Wake Forest University Health Sciences

Collaborator: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Source Wake Forest University Health Sciences
Brief Summary

There is growing interest in the utilization of transcranial magnetic stimulation (TMS) as a novel, non-pharmacologic approach to decreasing alcohol use among treatment-seeking individuals with Alcohol Use Disorder (AUD). The results of this study will be used to determine which of the 2 proposed TMS strategies has a larger effect on drinking behavior (% days abstinent, % heavy drinking days) as well as alcohol cue-reactivity in a 4 month period. These data will pave the way for TMS to be used as an innovative, new treatment option for individuals with AUD.

Detailed Description

Alcohol Use Disorder (AUD) is prevalent, devastating, and difficult to treat. The majority of the therapeutic approaches available to date have relied on pharmaceutical modulation or and/or psychotherapy. With a growing knowledge of the neural circuits that contribute to relapse in AUD, there is an emerging interest in developing a novel, neural-circuit specific therapeutic tool to enhance AUD treatment outcomes. The long term goal of the multidisciplinary research team is to develop an evidence-based brain stimulation treatment protocol which will improve AUD treatment outcomes. The competing neurobehavioral decision systems (CNDS) theory posits that in addiction, choice results from a regulatory imbalance between two decision-making systems (impulsive and executive) (25-27). These behavioral systems are functionally linked to two discrete frontal- striatal circuits which regulate limbic and executive control (28). Modulating these competing neural circuits (e.g. either dampening the limbic/impulsive system or amplifying the executive control system) may render alcohol users less vulnerable to relapse (43). These two frontal-striatal neural circuits - the limbic loop (ventromedial prefrontal cortex (vmPFC)-ventral striatum), and executive control loop (dorsolateral prefrontal cortex (dlPFC)-dorsal striatum) can be differentially stimulated by theta burst stimulation (TBS), a patterned form of transcranial magnetic stimulation (TMS) (15). Continuous TBS (cTBS) results in long term depression (LTD) of cortical excitability and intermittent TBS (iTBS) results in long term potentiation (LTP) (14).

Over the past 7 years, through the scaffolding of a National Institute on Alcohol Abuse and Alcoholism (NIAAA) P50 Center and a strong Brain Stimulation Research program, the multidisciplinary group of clinicians and neuroscientists have demonstrated 1) it is possible to differentially activate these circuits through TMS/Blood oxygenation level dependent (BOLD) imaging (15), 2) LTD-like TMS (cTBS) to the vmPFC (Strategy 1) decreases orbitofrontal cortex and ventral striatal/accumbens BOLD signal in heavy alcohol users (14), 3) cTBS also decreases alcohol cue reactivity in this population (17), and 4) in AUD patients currently enrolled in intensive outpatient treatment, 10 days of cTBS to the vmPFC is feasible, well-tolerated, increases 1 and 2 month retention rates, and attenuates limbic brain reactivity to alcohol cues after 1 month (17). While these studies provide a strong foundation for pursuing a larger multisite trial of cTBS, the CNDS theory and other alcohol TMS studies suggests that the dlPLC may also be a fruitful treatment target (25-27). Recently, a sham-controlled pilot study compared the efficacy of vmPFC cTBS (Strategy 1) to dlPFC iTBS (Strategy 2), and demonstrated that a single session of dlPFC iTBS had a greater effect on the brain response to alcohol cues that vmPFC cTBS (15). To resolve this gap in the literature, this protocol will propose a randomized, double-blind, sham-controlled clinical trial to evaluate the relative efficacy of these 2 strategies as novel tools to improve AUD treatment outcomes (e.g. percent days abstinent up to 4 months after treatment initiation). These outcomes will be measured with urine ethyl glucuronide (ETG) and carbohydrate-deficient transferrin (CDT) measurements. The brain reactivity to alcohol will also be used to evaluate the effect of these TBS treatments. The long-term vision is that TBS would be used as an adjuvant to behavioral treatment, enabling individuals to maximize the likelihood of behavioral change.

180 treatment-seeking men and women enrolled in Wake Forest University (WFU) associated clinics, including the Department of Psychiatry Outpatient Program and Comprehensive Cancer Center, will be randomized to receive 20 sessions (2x/day; 10 days, 20 min intersession interval) of either real or sham TBS to the vmPFC (Aim 1, Strategy 1) of left dlPFC (Aim 2, Strategy 2) while they are enrolled in the outpatient treatment program. Randomization will occur during the 1st week of the outpatient program. Real/Sham TBS will be delivered immediately before their outpatient therapy visit during weeks 2 & 3 of the program. Quantitative ETG will be collected daily. ETG and CDT will be collected monthly for 4 months. Additional assessments and brain reactivity to alcohol cues will be measured at 4 time points: before TMS treatment (Outpatient program, week 1), after TMS treatment (week 5), and at the 3 monthly Follow Up visits. Building on recent pilot data, the investigators will test the hypotheses that for both Strategy 1 & 2, real TBS will improve AUD treatment outcomes significantly more than sham. Analysis will be performed using repeated measures analysis of variance (ANOVA) on change scores from baseline for each visit. The main independent variable in the ANOVA will be time (visits on day 1, 6, 10), group (vmPFC vs. dlPFC TBS vs. sham) and their interaction.

Aim 1 (Strategy 1): Modulating the limbic system: vmPFC cTBS. The investigators will evaluate effect of vmPFC cTBS, relative to sham, on number of days abstinent (primary outcome) and heavy drinking days in 30 day intervals for 4 months. Participants will receive stimulation over the left frontal pole (EEG 10-20 system: FP1). This location has been used in previous studies in alcohol users which demonstrate vmPFC target engagement.

Aim 2 (Strategy 2): Modulating the executive system: dlPFC iTBS. The investigators will evaluate the effect of dlPFC iTBS, relative to sham, on the parameters listed. iTBS will be delivered over the left dlPFC (EEG 10-20 system: F3) as this location has also been validated to reliable result in target engagement by the investigators.

Exploratory Aim- Baseline alcohol cue reactivity as a mediator of TBS clinical response. The investigators will test the hypotheses that individuals with a higher ratio of (dlPFC-striatal)/(vmPFC-striatal) response to alcohol cues will be more likely to have a change in drinking after Strategy 2.

Overall Status Recruiting
Start Date May 26, 2020
Completion Date August 2024
Primary Completion Date August 2024
Phase N/A
Study Type Interventional
Primary Outcome
Measure Time Frame
Neuroimaging outcomes: change in drug cue reactivity as specified by changes in BOLD signal Baseline visit and 1 month follow-up
Percent days abstinent Through study completion, up to 4 month follow-up
Percentage of heavy drinking days Through study completion, up to 4 month follow-up
Secondary Outcome
Measure Time Frame
Changes in Craving Baseline visit, 1-4 month follow-ups
Enrollment 180
Condition
Intervention

Intervention Type: Device

Intervention Name: Real cTBS to the vmPFC

Description: This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key)

Arm Group Label: Real cTBS to the vmPFC

Intervention Type: Device

Intervention Name: Sham cTBS to the vmPFC

Description: This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the B60 coil.

Arm Group Label: Sham cTBS to the vmPFC

Intervention Type: Device

Intervention Name: Real iTBS to the dlPFC

Description: This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key).

Arm Group Label: Real iTBS to the dlPFC

Intervention Type: Device

Intervention Name: Sham iTBS to the dlPFC

Description: This will be delivered with the Magventure Magpro system; 600 pulses with the active sham coil (double blinded using the USB key). The MagVenture MagPro system has an integrated active sham that passes current through two surface electrodes placed on the skin beneath the B60 coil.

Arm Group Label: Sham iTBS to the dlPFC

Eligibility

Criteria:

Inclusion Criteria:

1. Age 21- 65 (to maximize participation from the cohort of individuals seeking alcohol treatment through intensive outpatient programs: Scalp- to-Cortex distance will be included as a covariate to calculate adjusted TMS dose given expected cortical atrophy in heavy alcohol users and older adults).

2. Meets the DSM V criteria for having a current AUD, determined by DSM- V criteria, using the Structured Clinical Interview for DSM-V.

3. Currently enrolled or scheduled to enroll in intensive outpatient program affiliated with Wake Forest University (WFU). Subjects who withdraw from the treatment program will no longer be allowed to participate in the study.

4. Consumption of more than 14 drinks (women) or 21 drinks (men) per week, with at least 2 heavy drinking days (defined as ≥ 4 drinks for women and ≥ 5 for men) during the 30-days prior to enrolling in the intensive outpatient program.

5. Able to read and understand questionnaires, assessments, and the informed consent.

6. No elevated risk of seizure (i.e., CIWA questionnaire <5, does not have a history of seizures, is not currently prescribed medications known to lower seizure threshold).

7. Not currently prescribed chlorpromazine, clozapine, olanzapine, aminophylline, pethidine, fentanyl due to their effects on cortical excitability.

8. No presence of metal objects in the head/neck.

9. No history of traumatic brain injury, including a head injury which resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage.

10. No history or current diagnosis of claustrophobia leading to significant clinical symptoms of anxiety.

Exclusion Criteria:

1. Currently meets DSM V criteria for moderate or severe substance use disorder in the past six months for any psychoactive substance other than alcohol.

2. Any psychoactive substance use (except marijuana and nicotine) within the last 30 days by self-report and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative (or decreasing) urine THC levels.

3. Meets DSM V criteria for current axis I disorders of panic disorder, obsessive-compulsive disorder, post traumatic stress syndrome, bipolar affective disorder, schizophrenia, dissociate disorders, eating disorders, and any other psychotic disorder or organic mental disorder. [Note: The inclusion of subjects with affective and anxiety disorders is essential because of the marked frequency of the co-existence of mood and other anxiety disorders among patients with AUD at large (including those in the outpatient program).

4. Has current suicidal ideation or homicidal ideation.

5. Is currently taking or initiates a medication known to affect alcohol intake and/or craving (e.g., disulfiram. naltrexone, acamprosate, topiramate). [Note: This exclusionary criterion is for scientific rather than safety or patient comfort reasons. Although some physicians involved in intensive outpatient programs prescribe naltrexone as applicable to patients, many individuals are not interested in medication management. In the pilot study included in the Research Strategy only 2 of the 42 individuals who enrolled in the study were given naltrexone at any point during the outpatient program or in aftercare].

6. Has a clinically significant medical problem such as cardiovascular, renal, GI, or endocrine problems that would impair participation.

7. Females of childbearing potential who are pregnant (by urine HCG), planning to become pregnant, nursing, or who are not using a reliable form of birth control.

8. Unstable living situation.

9. Suffers from chronic migraines.

10. Has metal placed above the neck.

11. Is at elevated risk of seizure (i.e., has a history of seizures, is currently prescribed medications known to lower seizure threshold).

12. History of claustrophobia.

13. History of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, and/or having ever been informed he/she has an epidural, subdural, or subarachnoid hemorrhage.

14. Presence of history of an unstable medical illness requiring planned medical/surgical intervention (e.g. chemotherapy, surgical procedure).

Gender: All

Minimum Age: 21 Years

Maximum Age: 65 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Colleen Hanlon, PhD Principal Investigator Wake Forest University
Overall Contact

Last Name: Colleen Hanlon, PhD

Phone: 843-792-5732

Email: [email protected]

Location
Facility: Status: Contact: Investigator: Wake Forest School of Medicine Colleen Hanlon, PhD 843-792-5732 [email protected] Colleen Hanlon, PhD Principal Investigator
Location Countries

United States

Verification Date

November 2019

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 4
Arm Group

Label: Real cTBS to the vmPFC

Type: Experimental

Description: Twenty sessions of real continuous Theta Burst Stimulation (cTBS) will be delivered to the left medial prefrontal cortex (mPFC) (1 train of stimulation over the left frontal pole (FP1); each train: 3 pulse bursts presented at 5Hz, 15 pulses/sec for 40 sec, 600 pulses/train, 110% rMT, MagPro; 600 pulses total)

Label: Sham cTBS to the vmPFC

Type: Sham Comparator

Description: Twenty sessions of sham continuous Theta Burst Stimulation (cTBS) will be delivered to the left medial prefrontal cortex (mPFC) (1 train of stimulation over the left frontal pole (FP1); each train: 3 pulse bursts presented at 5Hz, 15 pulses/sec for 40 sec, 600 pulses/train, 110% rMT, MagPro; 600 pulses total)

Label: Real iTBS to the dlPFC

Type: Experimental

Description: Twenty sessions of real intermittent Theta Burst Stimulation (iTBS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC) (20 trains of stimulation over dlPFC (middle frontal gyrus) (F3); each train: 3 pulse bursts presented at 5Hz, 15 pulses/ sec for 2 sec, 8 sec rest, 200 pulses/train; 110% rMT, MagPro; 600 pulses total)

Label: Sham iTBS to the dlPFC

Type: Sham Comparator

Description: Ten sessions of sham intermittent Theta Burst Stimulation (iTBS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC) (20 trains of stimulation over dlPFC (middle frontal gyrus) (F3); each train: 3 pulse bursts presented at 5Hz, 15 pulses/ sec for 2 sec, 8 sec rest, 200 pulses/train; 110% rMT, MagPro; 600 pulses total)

Patient Data No
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov